It is known that cancerous cells, such as tumor cells and leukemia cells, can be selectively purged from non-cancerous cells by photochemical methods. These methods are particularly useful in purging leukemia cells from a bone marrow graft before bone marrow transplantation. For instance, Merocyanine 540 (MC-540), a photosensitizing dye, has been used in photochemical purging of a patient's own (i.e., autologous) bone marrow graft. The effectiveness of MC-540-mediated photochemical purging, however, differs markedly in different leukemia cell lines.
Yamazaki and Sieber, found that the selective lethality of MC-540 for leukemia cells could be synergistically increased by using MC-540 in conjunction with an alkyl-lysophospholipid, rac-2-methyl-1-octadecyl-glycero-(3)-phosphocholine (ET-18-OCH3). See Bone Marrow Transplantation, 19, 629 (1997). These authors found that when photodynamic therapy (PDT) with MC-540 was followed by incubating the cells in ET-18-OCH3, the MC-540-mediated photoinactivation of leukemia cells was synergistically enhanced, while the treatment only minimally reduced the survival of normal granulocyte-macrophage progenitors.
On the basis of a comprehensive investigation involving more than 200 cell lines/types of melanoma, adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, and normal epithelial cells, Chen has demonstrated that enhanced mitochondrial membrane potential is a prevalent cancer cell phenotype. Ann. Rev. Cell Biol., 4, 155 (1988). Only approximately 2% of all cells tested so far disobey this apparently dominant precept. Higher electric potentials have also been observed in the plasma membrane of a variety of carcinoma cells as compared to normal epithelial cells. Because cell and mitochondrial membrane potentials are negative inside, extensively conjugated cationic molecules displaying appropriate structural features can be electrophoretically driven through these membranes and accumulate into the cytosol and inside cell mitochondria. The mitochondrial membrane potential is typically more than 60 mV higher in carcinoma cells than in normal epithelial cells. As a result, a number of cationic dyes preferentially accumulate and are retained in a variety of tumor cells, presumably because the mitochondria of these cells are not capable of excreting the dyes with the same efficiency as normal cells.
The preferential uptake and retention of a variety of extensively conjugated cationic compounds by tumor cells have motivated the examination of mitochondrial targeting as a relevant therapeutic strategy for both chemotherapy and photochemotherapy of neoplastic diseases. However, the structural parameters that control the accumulation of these compounds into cell mitochondria are not entirely understood, and the lack of a robust model to describe the relationship between molecular structure and mitochondrial accumulation has prevented mitochondrial targeting from becoming a more dependable therapeutic strategy. Described herein is a method of treating cancer that utilizes cationic, triarylmethane dye derivatives. In some of the methods disclosed herein the triarylmethane dye is a halogenated cationic triarylmethane dye. While the invention is not limited to a particular mode of action, it is thought that the destruction of tumor cells wrought by the method arises via selective accumulation of the dye in the mitochondria of tumor cells.
Since 1953, when Nussenzweig first described the inactivation of the protozoan parasite Trypanosoma cruzi (the vector responsible for Chagas' disease) by the cationic triarylmethane dye crystal violet (CV+), this triarylmethane dye has been extensively used in blood banks in underdeveloped areas to prevent transfusion-associated transmission of Chagas' disease (American trypanosomiasis). See Nussenzweig, et al., Hospital (Rio J), 44, 731 (1953). CV+ does not cause severe side effects in patients who receive blood treated with it, nor are the functions of blood cells jeopardized as a result of the chemoprophylaxis. The safety of CV+ is further demonstrated by its use as an anthelmintic, an antiseptic in umbilical cords of newborns and in burn patients.